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Glutathione peroxidase 4

Glutathione peroxidase 4 (GPX4) is a selenoprotein enzyme essential for cellular antioxidant defense, uniquely capable of reducing phospholipid and cholesterol hydroperoxides embedded in biological membranes to their corresponding alcohols using reduced glutathione (GSH) as a cofactor, thereby preventing lipid peroxidation and maintaining redox homeostasis.^[1] Discovered in 1982 and characterized as phospholipid hydroperoxide glutathione peroxidase (PHGPx), GPX4 stands out among the glutathione peroxidase family for its monomeric structure and broad substrate specificity, which includes complex hydroperoxides not accessible to other family members.^[1] GPX4 exists in three main isoforms—cytosolic (cGPX4), mitochondrial (mGPX4), and nuclear/spermatogenic (nGPX4)—generated from a single gene on human chromosome 19p13.3 through alternative transcription start sites and RNA processing, each localized to specific cellular compartments to fulfill distinct protective roles.^[2] The enzyme's active site features a catalytic tetrad comprising selenocysteine (Sec46), glutamine (Gln81), tryptophan (Trp136), and asparagine (Asn137), enabling a ping-pong reaction mechanism where the selenol group is oxidized to selenenic acid by the hydroperoxide, followed by reduction via two GSH molecules to regenerate the active form and produce glutathione disulfide (GSSG).^[1] With a molecular weight of approximately 22 kDa and 197 amino acids in its cytosolic form, GPX4's selenocysteine residue imparts superior redox reactivity, making its activity highly dependent on selenium availability.^[3] As the central negative regulator of ferroptosis—an iron-dependent, lipid peroxidation-driven form of regulated cell death—GPX4 inhibition or depletion triggers this process in diverse cell types, highlighting its indispensable role in embryonic development, as global GPX4 knockout is embryonic lethal in mice by day 7.5.^[2] Beyond ferroptosis, GPX4 influences autophagy by modulating reactive oxygen species (ROS) levels, where its degradation via selective autophagy pathways enhances ferroptotic sensitivity, and it also contributes to sperm chromatin condensation and mitochondrial integrity through its isoform-specific functions.^[2] Dysregulation of GPX4 is implicated in numerous pathologies, including neurodegenerative diseases like Alzheimer's and Parkinson's, where its loss exacerbates neuronal lipid peroxidation and cognitive decline; cancers such as triple-negative breast cancer and colorectal tumors, in which GPX4 overexpression confers therapy resistance but targeted inhibition induces ferroptosis for potential treatment; cardiovascular conditions like atherosclerosis and ischemia-reperfusion injury, mitigated by GPX4 activation; and rare genetic disorders such as Sedaghatian-type spondylometaphyseal dysplasia caused by the R152H mutation.^[3] Additionally, GPX4 protects against inflammation in sepsis and immune disorders by suppressing pyroptosis and ferroptosis in myeloid cells, underscoring its therapeutic promise as a target for modulating oxidative stress-related diseases.^[2]

Discovery and Basics

Discovery

Glutathione peroxidase 4 (GPX4), initially known as the peroxidation-inhibiting protein, was first purified in 1982 from pig liver extracts by researchers at the University of Padua, including Fulvio Ursini and colleagues, who identified it as a novel enzyme capable of protecting liposomes and biomembranes from peroxidative degradation.^[4] This protein exhibited glutathione peroxidase activity specifically toward phosphatidylcholine hydroperoxides, distinguishing it from previously known glutathione peroxidases like GPX1, which primarily reduce soluble hydroperoxides such as hydrogen peroxide.^[4] Initial biochemical assays involved monitoring the reduction of linoleic acid hydroperoxide in phosphatidylcholine liposomes, where the enzyme's activity was dependent on reduced glutathione and inhibited by selenite, highlighting its unique substrate specificity for complex lipid hydroperoxides embedded in membranes.^[4] In 1985, Ursini and co-workers further characterized this enzyme as a selenoprotein, naming it phospholipid hydroperoxide glutathione peroxidase (PHGPx) due to its ability to directly reduce hydroperoxy groups within phospholipid molecules.^[5] The identification of selenocysteine at its active site confirmed its status as a hallmark selenoprotein, essential for its catalytic function in preventing lipid peroxidation in biological membranes.^[5] These early studies, conducted through purification to homogeneity and activity assays on dilinoleoyl phosphatidylcholine hydroperoxides, established GPX4's distinct role among the GPX family in safeguarding against oxidative damage in lipid-rich environments like testes and liver tissues.^[5] The connection of GPX4 to regulated cell death pathways emerged later with the discovery of ferroptosis, an iron-dependent form of non-apoptotic cell death characterized by lipid peroxidation, reported in 2012 by Scott J. Dixon and Brent R. Stockwell at Columbia University.^[6] Building on this, a 2014 study from the same group identified GPX4 as a central negative regulator of ferroptosis, demonstrating that its inhibition by compounds like RSL3 triggers lethal lipid peroxide accumulation, while GPX4 overexpression suppresses ferroptosis induced by various agents. This milestone linked GPX4's antioxidant function to preventing oxidative cell death, reshaping understanding of its physiological importance beyond basic peroxide detoxification.

Gene and Nomenclature

The GPX4 gene, officially symbolized as GPX4, is located on the short arm of human chromosome 19 at position 19p13.3, spanning approximately 2.8 kb of genomic DNA.^[7]^[8] This gene encodes the 197-amino acid protein glutathione peroxidase 4, a member of the selenoprotein family essential for antioxidant defense.^[7]^[9] Historically, the enzyme was first identified and purified from porcine tissues in 1982 and initially named phospholipid hydroperoxide glutathione peroxidase (PHGPx) due to its unique ability to reduce hydroperoxides in phospholipids.^[10] Over time, as part of the broader glutathione peroxidase family, the nomenclature was standardized to GPX4 to reflect its classification among the eight human GPX genes, with the "4" designating its specific isoform.^[11] This unification emphasizes its role as a selenoprotein, where selenium is incorporated as the catalytic residue selenocysteine (Sec).^[12] The GPX4 gene consists of seven exons interrupted by six introns, with the coding sequence distributed across these exons to produce the mature protein transcript.^[7]^[8] The selenocysteine residue, critical for enzymatic activity, is encoded by a UGA codon at position 46 in the human protein sequence.^[12] This insertion is directed by a selenocysteine insertion sequence (SECIS) element, a stem-loop structure located in the 3' untranslated region (UTR) of the GPX4 mRNA, which recruits trans-acting factors to recode the UGA from a stop signal to Sec.^[13] Evolutionarily, GPX4 is highly conserved across eukaryotes, with orthologs identified in 163 species ranging from yeast to mammals, underscoring its fundamental role in cellular redox homeostasis.^[8] The conservation extends to the catalytic selenocysteine motif and the SECIS-dependent insertion machinery, which are preserved in eukaryotic selenoproteins to ensure peroxide reduction capabilities.^[14]

Structure and Isoforms

Protein Structure

Glutathione peroxidase 4 (GPX4) is a monomeric selenoprotein with a molecular mass of approximately 22 kDa and 197 amino acid residues in its mature cytosolic form.^[10] The enzyme's core structure consists of four α-helices positioned near the protein surface and seven β-strands, five of which form a central β-sheet, adopting a thioredoxin-like fold typical of the glutathione peroxidase family.^[10] A flexible N-terminal region, particularly prominent in the mitochondrial isoform after cleavage of the targeting sequence, enables GPX4 to interact with lipid membranes, positioning it to access embedded hydroperoxides. The catalytic active site is defined by a conserved tetrad comprising selenocysteine at position 46 (Sec46), glutamine at position 81 (Gln81), tryptophan at position 136 (Trp136), and asparagine at position 137 (Asn137), where these residues stabilize redox intermediates through hydrogen bonding networks. The selenium atom in Sec46 is pivotal for active site geometry, facilitating nucleophilic attack on peroxides and enabling efficient electron transfer during catalysis.^[15] High-resolution crystal structures of human GPX4, such as the selenocysteine-to-glycine mutant (PDB entry 2GS3) resolved at 2.3 Å, illustrate the compact monomeric fold and open active site cleft, with the catalytic tetrad residues converging to form a solvent-accessible pocket.^[16] More recent structures of the wild-type selenocysteine-containing form (e.g., PDB entry 6ELW at 1.3 Å resolution) confirm the selenium's coordination, highlighting its role in maintaining the site's reactivity without additional stabilizing loops. In comparison to other glutathione peroxidases (GPX1–3, GPX5–6), which form homotetramers with a rigid, surface-exposed loop restricting substrate access, GPX4's monomeric architecture and less constrained active site confer broader substrate specificity, particularly for complex lipid hydroperoxides. This structural divergence underscores GPX4's specialized adaptation for membrane-associated antioxidant defense.^[10]

Isoforms and Subcellular Distribution

Glutathione peroxidase 4 (GPX4) exists in three primary isoforms in mammals, generated through alternative transcription start sites within the GPX4 gene. The cytosolic isoform (cGPX4), also known as the short form, is produced from exon 1a using a downstream translation initiation site, resulting in a protein lacking a mitochondrial targeting sequence and consisting of 197 amino acids. The mitochondrial isoform (mGPX4), or long form, arises from the same exon 1a but utilizes an upstream initiation codon, incorporating an N-terminal 27-amino-acid extension that directs it to mitochondria, with the precursor comprising 226 amino acids (mature form ~199 aa after cleavage). The nuclear isoform (nGPX4) is transcribed from an alternative first exon (exon 1b), featuring a short N-terminus with a nuclear localization signal and 168 amino acids. All isoforms contain a selenocysteine residue at the active site, essential for their peroxidative activity.^[17]^[18] These isoforms exhibit distinct subcellular distributions that align with their structural features. The cGPX4 isoform is ubiquitously expressed in the cytosol of somatic tissues and is indispensable for embryonic survival and protection against oxidative damage, with evidence from mouse models showing that its targeted expression rescues lethality in GPX4-null embryos. The mGPX4 isoform localizes primarily to mitochondria, where it safeguards inner membrane lipids from peroxidation, particularly in tissues like the testes and during spermatogenesis; its absence in mice leads to impaired hindbrain development and male infertility. The nGPX4 isoform is predominantly nuclear, binding to sperm chromatin via lysine- and arginine-rich domains to maintain DNA integrity, though it is also implicated in regulating gene expression under oxidative stress in other cell types.^[19]^[17]^[18] This isoform pattern has been well-characterized in mice and rats, with the short cytosolic form predominant in somatic tissues and the long mitochondrial form enriched in testes. In humans, the GPX4 gene structure supports analogous isoform generation and distribution, though direct functional verification of all isoforms remains ongoing. Expression of GPX4 isoforms is upregulated in response to oxidative stress through the Nrf2 transcription factor pathway, which binds to antioxidant response elements in the GPX4 promoter to enhance transcription across isoforms.^[19]^[18]^[20]

Function and Mechanism

Biochemical Reaction

Glutathione peroxidase 4 (GPX4) catalyzes the reduction of lipid hydroperoxides, particularly phospholipid hydroperoxides (PLOOH), to their corresponding alcohols using reduced glutathione (GSH) as the reductant. The overall reaction is:

\text{PLOOH} + 2\text{GSH} \rightarrow \text{PL-OH} + \text{GSSG} + \text{H}_2\text{O}

where GSSG is oxidized glutathione. This process is mediated by the selenocysteine residue at position 46 (Sec46) in the enzyme's active site, which imparts high catalytic efficiency.^[10] The catalytic mechanism proceeds via a ping-pong bi-bi pathway. In the first step, the deprotonated selenol group (Se⁻) of Sec46 launches a nucleophilic attack on the peroxide oxygen of PLOOH, cleaving the O-O bond and forming a selenenic acid intermediate (Enz-SeOH) while releasing the alcohol product (PL-OH). Subsequently, the selenenic acid intermediate reacts with the thiol group of the first GSH molecule to form a selenodisulfide intermediate (Enz-Se-SG) and water. Finally, a second GSH molecule reduces the selenodisulfide, regenerating the selenol (Enz-SeH) and yielding GSSG.^[10]^[21] GPX4 displays high substrate specificity for phospholipid hydroperoxides embedded in membranes, distinguishing it from other glutathione peroxidases that prefer soluble hydroperoxides like H₂O₂. Kinetic parameters include a K_m for GSH of approximately 1 mM and for hydroperoxides of around 10 μM, reflecting efficient peroxide scavenging at physiological concentrations.^[22]^[10] The GSSG byproduct is recycled to GSH by the NADPH-dependent enzyme glutathione reductase, ensuring a sustained supply of the reductant and coupling GPX4 activity to the cellular redox state.^[10]

Role in Cellular Protection

Glutathione peroxidase 4 (GPX4) serves as a primary antioxidant enzyme by reducing lipid hydroperoxides, particularly phospholipid hydroperoxides embedded within cellular membranes, thereby preventing the propagation of lipid peroxidation chain reactions that could compromise membrane integrity and lead to cellular dysfunction.^[23] This activity is crucial for maintaining redox homeostasis, as unchecked lipid peroxidation generates toxic byproducts like malondialdehyde and 4-hydroxynonenal, which can damage proteins and DNA.^[23] Unlike general antioxidants, GPX4's specificity for complex lipid substrates allows it to directly intervene at the site of oxidative damage in biomembranes, such as mitochondria, where it repairs peroxidized cardiolipin to inhibit downstream apoptotic signaling.^[24] GPX4 integrates seamlessly with the cellular glutathione system, utilizing reduced glutathione (GSH) as a cofactor to catalyze the reduction of hydroperoxides to less reactive alcohols, which helps sustain low levels of hydrogen peroxide (H₂O₂) and lipid-derived reactive oxygen species (ROS).^[1] This partnership is indispensable for protecting vulnerable cell types; for instance, in spermatogenesis, GPX4 ensures sperm maturation and viability by shielding developing germ cells from oxidative stress, with its selenoprotein form cross-linking to structural proteins in the sperm midpiece and nucleus. Deficiency in GPX4 leads to impaired sperm development and male infertility, underscoring its non-redundant role in reproductive tissues where other peroxidases cannot compensate. In response to oxidative stressors, GPX4 expression is upregulated through pathways like Nrf2 activation, enhancing cellular resilience in environments with elevated ROS, such as during exposure to radiation or chemical oxidants.^[25] This adaptive response protects against ischemia-reperfusion injury by mitigating lipid peroxidation in tissues like the heart and kidney, where transient GPX4 overexpression reduces mitochondrial damage and preserves organ function.^[26] GPX4's unique substrate specificity for membrane-bound lipids distinguishes it from other glutathione peroxidases, such as GPX1, which primarily target soluble peroxides and cannot substitute for GPX4 in preventing membrane-specific oxidative harm.^[23]

Biological and Physiological Roles

Studies in Animal Models

Global knockout of the Gpx4 gene in mice results in embryonic lethality between embryonic days 7.5 and 8.5, characterized by severe developmental defects including disorganized germ layers and extensive lipid peroxidation in embryonic tissues. This phenotype underscores the essential role of GPX4 in early embryonic protection against oxidative damage, as homozygous null embryos exhibit markedly elevated levels of phospholipid hydroperoxides compared to wild-type littermates. Conditional knockout models have revealed tissue-specific consequences of GPX4 deficiency. In brain-specific knockouts targeting forebrain neurons, adult mice develop progressive cognitive impairment, hippocampal neurodegeneration, and neuronal loss within weeks of induction, accompanied by mitochondrial dysfunction and increased oxidative stress markers.^[27] Similarly, neuron-specific ablation in motor neurons leads to rapid paralysis, widespread neurodegeneration, and death within 1-2 weeks, highlighting GPX4's critical neuroprotective function.^[28] Testis-specific knockout in spermatocytes causes complete male infertility, with affected mice showing disrupted spermiogenesis, midpiece deformities in spermatozoa, and elevated protein thiol content despite normal mating behavior.^[29] Heterozygous Gpx4 mice, which express approximately 50% of wild-type GPX4 levels across tissues, exhibit an extended median lifespan of 1029 days compared to 963 days in wild-type controls, associated with reduced incidence of age-related pathologies such as lymphoma.^[30] These mice also display decreased sensitivity to oxidative insults, suggesting that moderate GPX4 reduction enhances apoptosis in damaged cells, thereby promoting longevity.^[30] Overexpression studies demonstrate protective effects of elevated GPX4. Transgenic mice overexpressing GPX4 in apolipoprotein E-deficient backgrounds show reduced lipid peroxidation in arterial walls, though a 2024 study indicates no significant change in atherosclerotic lesion size or plaque development.^[31]^[32] In models of cardiac ischemia-reperfusion injury, mitochondria-targeted GPX4 overexpression preserves cardiac contractile function, maintains electron transport chain complex activities, and attenuates mitochondrial damage post-injury.^[33]

Regulation of Ferroptosis

Ferroptosis is an iron-dependent form of regulated cell death driven by the accumulation of lipid peroxides on cellular membranes. Glutathione peroxidase 4 (GPX4) serves as the central suppressor of ferroptosis by catalyzing the reduction of toxic lipid hydroperoxides to non-reactive lipid alcohols, utilizing glutathione (GSH) as the reducing substrate. This enzymatic activity directly prevents the propagation of lipid peroxidation chains, thereby maintaining membrane integrity and averting ferroptotic execution.01544-4) Direct inhibition of GPX4 activity, exemplified by the small-molecule inhibitor RSL3, potently induces ferroptosis across diverse cell types by blocking the enzyme's selenocysteine-dependent active site, leading to unchecked lipid peroxidation. This ferroptosis susceptibility is tightly linked to the system xc^−/GSH axis, wherein the cystine-glutamate antiporter (composed of SLC7A11 and SLC3A2) facilitates cystine uptake for intracellular reduction to cysteine, the rate-limiting precursor for GSH biosynthesis. Depletion of GSH through system xc^− blockade (e.g., by erastin) impairs GPX4 function, rendering cells vulnerable to ferroptosis even without direct GPX4 targeting.01544-4)^[34] GPX4's ferroptosis suppression involves functional crosstalk with acyl-CoA synthetase long-chain family member 4 (ACSL4), which selectively incorporates polyunsaturated fatty acids, such as arachidonate, into membrane phospholipids to generate peroxidation-prone lipid substrates. High ACSL4 expression enhances cellular sensitivity to GPX4 inhibition by expanding the pool of oxidizable lipids, while ACSL4 deficiency confers resistance to ferroptosis inducers like RSL3, underscoring a pro-ferroptotic role complementary to GPX4's protective function.^[35] Transcriptional regulation of GPX4 expression modulates ferroptosis thresholds, with the tumor suppressor p53 acting as a bidirectional controller. In its canonical role, p53 promotes ferroptosis by transcriptionally repressing SLC7A11, thereby limiting GSH availability and indirectly compromising GPX4 activity; however, p53 can also suppress ferroptosis under certain stresses by upregulating genes that bolster the GPX4-GSH pathway. Conversely, the redox-sensitive transcription factor NRF2 (NFE2L2) potently induces GPX4 expression as part of its antioxidant program, directly counteracting ferroptosis by enhancing hydroperoxide detoxification capacity. NRF2 activation, often in response to oxidative insults, thus positions GPX4 as a key effector in NRF2-mediated ferroptosis resistance.^[36]^[37] Recent investigations in 2024 have elucidated GPX4's involvement in cold-induced ferroptosis using deficient cellular models. In GPX4-knockout Syrian hamster cells, prolonged exposure to 4°C triggers ferroptosis characterized by lipid peroxidation and cell death after approximately 5 days, a process mitigated by ferroptosis inhibitors like ferrostatin-1 or iron chelators such as deferoxamine. These findings suggest that GPX4 deficiency disrupts adaptive mechanisms against cold stress, potentially linking ferroptosis to mammalian hibernation tolerance.^[38]

Disease Implications

Associated Pathologies

Mutations in the GPX4 gene, particularly truncating variants, have been identified as the cause of Sedaghatian-type spondylometaphyseal dysplasia (SSMD), a rare autosomal recessive disorder characterized by severe metaphyseal chondrodysplasia, cardiac arrhythmias, and neonatal lethality.^[39] Biallelic loss-of-function mutations in GPX4 disrupt selenoprotein biosynthesis, leading to impaired lipid peroxidation defense and embryonic or perinatal death in affected individuals.^[40] Additional GPX4 mutations, including dominant-negative variants like Gpx4_U46S, contribute to male infertility by causing structural defects in spermatozoa.^[41]^[17] In cancer, GPX4 overexpression is observed in various tumors, where it enhances cell survival by mitigating lipid peroxidation and ferroptotic stress, thereby promoting tumor progression and resistance to therapy.^[42] Conversely, many mesenchymal-state cancers, including those from ovarian, kidney, and triple-negative breast origins, exhibit a synthetic lethal dependency on GPX4, rendering them selectively vulnerable to ferroptosis inducers that inhibit its activity.^[43] This dependency arises from the heightened lipid peroxidation burden in mesenchymal cancer cells, making GPX4 inhibition a promising strategy for targeting therapy-resistant populations.^[44] GPX4 dysfunction is implicated in neurodegeneration, with reduced GPX4 levels reported in the brains of patients with Alzheimer's disease (AD) and Parkinson's disease (PD), correlating with increased oxidative stress and ferroptotic neuronal death.^[45] In AD, GPX4 deficiency exacerbates amyloid-β aggregation and tau hyperphosphorylation by promoting iron-mediated lipid peroxidation, while in PD, it contributes to dopaminergic neuron loss through impaired glutathione-dependent peroxide reduction.^[46]^[47] Beyond these, GPX4 alterations are linked to male infertility, where mitochondrial GPX4 disruption results in severe sperm midpiece abnormalities, impaired motility, and oligospermia due to defective mitochondrial morphology and increased peroxide damage.^[48] In atherosclerosis, reduced GPX4 activity drives endothelial and macrophage ferroptosis, exacerbating plaque inflammation and lipid accumulation through unchecked oxidized low-density lipoprotein-induced peroxidation.^[49] Recent studies from 2023–2025 highlight GPX4's role in non-alcoholic fatty liver disease (NAFLD), now termed metabolic dysfunction-associated steatotic liver disease, where GPX4 downregulation promotes hepatocyte ferroptosis, fibrosis progression, and transition to hepatocellular carcinoma via dysregulated iron metabolism and lipid peroxidation.^[50] Similarly, in aging, declining GPX4 expression accelerates vascular smooth muscle cell senescence and arterial remodeling by enhancing pro-ferroptotic signaling, contributing to age-related vascular stiffness and chronic inflammation.^[51]

Clinical and Therapeutic Relevance

Glutathione peroxidase 4 (GPX4) levels serve as a potential biomarker for oxidative stress in various malignancies, where elevated expression correlates with favorable prognosis in diffuse large B-cell lymphoma (DLBCL) patients, aiding in diagnostic stratification. In broader cancer contexts, GPX4 mutation burden has been linked to patient survival outcomes across multiple tumor types, supporting its role in prognostic assessments. In neurodegenerative disorders, reduced GPX4 activity is associated with heightened oxidative stress and ferroptosis vulnerability in neurons, positioning it as an indicator for disease progression in conditions like Alzheimer's and Parkinson's. Genetic screening for GPX4 mutations is clinically relevant for diagnosing rare disorders such as Sedaghatian-type spondylometaphyseal dysplasia (SSMD), an autosomal recessive condition caused by truncating or missense variants that impair enzyme function, enabling early identification in affected neonates.^[52]^[53]^[17]^[54]^[39]^[55] Inhibitors targeting GPX4, such as RSL3, directly suppress its enzymatic activity to induce ferroptosis, showing promise in eliminating cancer cells across various lineages by promoting lipid peroxidation. Similarly, FIN56 triggers GPX4 protein degradation via autophagy-lysosomal pathways, enhancing ferroptosis sensitivity in tumor models and offering a complementary mechanism for therapy. These agents are particularly effective against drug-tolerant persister cells, non-genetic subpopulations that survive conventional treatments; post-2020 studies demonstrate that RSL3 and FIN56 selectively eradicate these persisters in colorectal and other cancers by exploiting their reliance on GPX4 for survival.^[56]^[57]^[58]^[59] Selenium supplementation enhances GPX4 expression and activity by providing the essential selenocysteine cofactor, mitigating oxidative stress in clinical settings like chemoradiotherapy for esophageal cancer, where it improves patient tolerance without significant toxicity. NRF2 agonists, such as sulforaphane, upregulate GPX4 transcription via antioxidant response elements, potentially protecting against oxidative damage in non-malignant contexts, though their application in cancer therapy requires caution due to NRF2's role in promoting tumor resistance.^[60]^[61]^[20]^[62] As of 2025, Phase I and II clinical trials are exploring GPX4 inhibitors and ferroptosis inducers like RSL3 analogs for refractory cancers, including glioblastoma and triple-negative breast cancer, often in combination with radiotherapy or immunotherapy to target resistant subpopulations. These trials highlight efficacy in overcoming therapy resistance but face challenges in achieving specificity, as off-target ferroptosis in normal tissues can lead to toxicity, necessitating refined delivery strategies.^[63]^[64]

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Identification of genes supporting cold resistance of mammalian cells
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Targeting dependency on the GPX4 lipid peroxide repair pathway ...
This common mesenchymal character partially explained the extension of GPX4 dependency from high-mesenchymal cancers to persister cells; the underlying ...
[45]
Targeting Dependency on the GPX4 Lipid Peroxide Repair Pathway ...
Mar 27, 2018 · This common mesenchymal character partially explained the extension of GPX4 dependency from high-mesenchymal cancers to persister cells; the ...
[46]
The Role of Cellular Defense Systems of Ferroptosis in Parkinson's ...
Sep 14, 2023 · Decreased GPX4 in forebrain neurons and spinal cord motor neurons leads to a loss of spatial learning and memory function in mice and ...
[47]
Ferroptosis in the Pathogenesis of Alzheimer's Disease
Jan 30, 2024 · Elevated levels of iron contribute to the formation of protein aggregates, such as hyperphosphorylated tau. Iron increase-induced may lead to ...Ferroptosis In The... · Lipid Peroxidation And Its... · The Ferroptosis Therapeutic...<|separator|>
[48]
Insight into the potential role of ferroptosis in neurodegenerative ...
GPX4 knockout mice were shown to have significant hippocampal neuronal loss and cognitive impairment (Yoo et al., 2010; Hambright et al., 2017). A diet ...
[49]
Mitochondrial glutathione peroxidase 4 disruption causes male ...
We show that deletion of mitochondrial GPx4 (mGPx4) allows both normal embryogenesis and postnatal development, but causes male infertility.Missing: specific | Show results with:specific
[50]
Ferroptosis: the potential value target in atherosclerosis - Nature
Aug 10, 2021 · Chronic iron overload intensifies atherosclerosis in apolipoprotein E deficient mice: role of oxidative stress and endothelial dysfunction.Missing: heterozygous lifespan
[51]
Emerging role of ferroptosis in metabolic dysfunction-associated ...
In normal liver physiology, the GPX4-GSH axis (fed by the transsulfuration pathway) is indispensable to prevent spontaneous hepatocyte ferroptosis. In MASLD ...
[52]
Pro-ferroptotic signaling promotes arterial aging via vascular smooth ...
Feb 16, 2024 · Here, we show that pro-ferroptosis signaling drives VSMCs senescence to accelerate vascular NAD + loss, remodelling and aging.
[53]
GPX4 is a potential diagnostic and therapeutic biomarker associated ...
Feb 15, 2024 · GPX4 can serve as a potential therapeutic and diagnostic marker for DLBCL. GPX4's high expression can lead to a good prognosis in DLBCL patients.Missing: screening | Show results with:screening
[54]
Ferroptosis's Master Switch GPX4 emerges as universal biomarker ...
Oct 9, 2025 · Furthermore, we detected a correlation between the mutation burden of GPX4 across different types of cancer and patient survival outcomes.Missing: screening | Show results with:screening
[55]
The role of glutathione peroxidase 4 in neuronal ferroptosis and its ...
Oct 15, 2024 · GPx4 overexpression significantly reduces lipid peroxidation neuron death, ameliorates brain edema and neurological deficits after SAH. (Gao et ...Missing: values | Show results with:values
[56]
Development of therapies for rare genetic disorders of GPX4
Oct 23, 2021 · The human GPX4 gene contains seven exons and six introns and can be expressed as three isoforms of the protein, mitochondrial (mGPX4, UniProt ...
[57]
Ferroptosis: An emerging therapeutic opportunity for cancer - PMC
Indeed, RSL3 and other small-molecule GPX4 inhibitors can induce ferroptosis in not only cultured cancer cells but also tumor xenografts implanted in mice.
[58]
Fin56-induced ferroptosis is supported by autophagy-mediated ...
Oct 29, 2021 · Fin56, a type 3 ferroptosis inducer, triggers ferroptosis by promoting glutathione peroxidase 4 (GPX4) protein degradation via a not fully understood pathway.
[59]
Glutathione Peroxidase 4 as a Therapeutic Target for Anti-Colorectal ...
We investigated the efficacy and mechanism of ferroptosis inducers RSL3 and FIN56 on persister cells, which are glutathione peroxidase 4 inhibitors. In the ...
[60]
Drug-tolerant persister cancer cells - ScienceDirect.com
In addition, survival of DTPC cells heavily relied on lipid hydroperoxidase GPX4, and inhibitors, such as RSL3 or FIN56, reduced GPX4 activity to trigger ...
[61]
Effects of selenium supplementation on expression of glutathione ...
GPX4 protein level was also low in H1703 cells, but was markedly increased by selenium supplementation (48-fold). These results confirm a role for selenium in ...
[62]
Effects of selenium supplementation on concurrent ... - Frontiers
Feb 1, 2023 · We conducted a randomized, double-blind, and placebo-parallel controlled clinical trial to evaluate the effects and safety of Se supplementation ...
[63]
An update of Nrf2 activators and inhibitors in cancer prevention ...
Jun 30, 2022 · In this review, we describe lately discovered Nrf2 inducers and inhibitors, and their chemopreventive and/or anticancer activities.Missing: boost | Show results with:boost
[64]
Harnessing ferroptosis to transform glioblastoma therapy ... - Nature
Oct 7, 2025 · Future clinical trials integrating GPX4 inhibitors with radiotherapy may define therapeutic windows that disrupt recurrence-driving ...
[65]
Unveiling the therapeutic potential of ferroptosis in lung cancer
Apr 10, 2025 · Inhibition of GPX4 in lung cancer cells leads to ferroptosis, enhancing the efficacy of existing treatments and overcoming drug resistance [13].